Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
  • C07D487/14—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
  • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D495/04—Ortho-condensed systems

Definitions

• This invention relates to a novel compound having a strong antitumor activity, and more particularly to a specific isoindole derivative represented by general formula [1] which will be shown hereinafter or a salt thereof.
• the chemotherapy in an oncological field has been improved over recent several tens of years to such an extent that some cancers such as leukemia and the like have become curable with only a chemotherapeutic agent with a high cure rate.
• the cure rate against the cancer of internal organs such as colon, stomach, lung and the like which are now considered to be the most important target for the chemotherapy, is very low.
• This problem is now the most important and urgent matter for a civilization to solve.
• the resistance acquisitions of tumor cells to chemotherapeutic agents and the toxicities of chemotherapeutic agents against normal cells are also serious problems. Under these circumstances, the development of new antitumor drugs which overcome the deficiencies of currently used antitumor drugs is greatly desired.
• halogen atom means a fluorine, chlorine, bromine or iodine atom
• the term “lower alkyl group” means a C 1-5 alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl or the like
• alkenyl group means a C 2-22 alkenyl group such as vinyl, allyl, butenyl, decenyl, hexadecenyl, heptadecnyl, octadecenyl or the like
• the term “lower alkylene group” means a C 1-5 alkylene group such as methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene, 1-methyltrimethylene or the like
• aryl group means a phenyl, tolyl or naphthyl
• the substituents of the substituted lower alkyl, alkenyl, lower alkylthio, cycloalkyl, aryl, aryloxy, carbamoyloxy, acyl, heterocyclic carbonyloxy or heterocyclic group in the definitions of R 1 and R 3 ; the substituents of the substituted lower alkyl, aryl, aralkyl, carbamoyl or acyl group in the definition of R 2 ; the substituents of the substituted lower alkyl, cycloalkyl, aralkyl, acyl or aryl group in the definitions of R 4 and R 5 and the substituents of the substituted nitrogen-containing heterocyclic group which R 4 and R 5 form with the nitrogen atom to which they are bonded include halogen atoms, lower alkyl groups, lower alkoxy groups, di-lower alkylamino groups, cycloalkyl groups, aryl groups, aralkyl groups, unprotected or protected hydroxy
• each of R 1 to R 5 has a hydroxyl group, it may be protected with a usually known protective group.
• the protective groups of the protected amino, carboxyl and hydroxyl groups include commonly used protective groups, and specifically those described in Theodora W. Green, Protective Groups in Organic Synthesis, published by John Wiley & Sons, Inc., (1981), Japanese Patent Application Kokoku No. 52,755/85 and the like.
• the salts of the isoindole derivatives of general formula [1] may be conventional salts at basic group such as amino group or the like or at acidic group such as hydroxyl or carboxyl group or the like.
• the salts at basic group include, for example, salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like; salts with organic carboxylic acids such as tartaric acid, formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid and the like; salts with sulfonic acids such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid, naphthalenesulfonic acid and the like; etc.
• the salts at acidic groups include salts with alkali metals such as sodium, potassium and the like; salts with alkaline earth metals such as calcium, magnesium and the like; ammonium salts; salts with nitrogen-containing organic bases such as trimethylamine, triethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorph
• this group may form a salt with a halide anion, a lower alkylsulfonyloxy anion, or an unsubstituted or lower alkyl- or halogen-substituted arylsulfonyloxy anion, or the like.
• isoindole derivative of general formula [1] and a salt thereof may form an inner salt.
• this invention includes all of the isomers. Moreover, this invention includes hydrates, solvates and various crystal forms thereof, too.
• the isoindole derivatives of general formula [1] and their salts can be produced by processes known per se or their appropriate combinations, for example, according to the following production routes: ##STR10## where R 1 , R 2 , R 3 , G, Y and Z have the same meanings as defined above, G 1 represents an oxygen or sulfur atom or a group of the formula, ##STR11## in which R 2 has the same meaning as defined above; R 2a is the unsubstituted or substituted lower alkyl, aralkyl or acyl group mentioned in the definition of R 2 ; R 6b represents the unsubstituted or substituted aryl group mentioned in the definition of R 6 stated hereinafter; R 10 represents an unsubstituted or substituted lower alkyl, alkenyl, cycloalkyl, aryl, aryloxy, aralkyl, lower alkylamino, di-lower alkylamino or heterocyclic group; R 11 represents an unsubstituted
• the trialkylamine and the cyclic amine are, respectively, a trialkylamine capable of forming the trialkylammonio group explained as to Z and a cyclic amine capable of forming the cyclic ammonio group explained as to Z.
• the removable group in the definition of D includes halogen atoms, acyloxy groups, arylsulfonyloxy groups, lower alkoxysulfonyloxy groups and the like which are usually known as removable groups.
• R 2a , R 6b , R 10 , R 11 and R 11a include those mentioned as to R 1 to R 5 .
• a compound of general formula [1] is reacted with a compound of general formula [3] in the presence or absence of a solvent to obtain a compound of general formula [1].
• This reaction is effected by per se known processes or their appropriate combinations, for example, according to the method described on pages 973-975 of Organic Syntheses, Col. Vol. V or a method similar thereto.
• the solvent to be used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; halogenated hydrocarbons such as chloroform, methylene chloride, dichloroethane and the like. These solvents may be used alone or in admixture of two or more.
• the above reaction may be effected in the presence of a base.
• the base which may be optionally used in the above reaction includes, for example, inorganic bases such as alkali hydrogencarbonates, alkali carbonates, alkali hydroxides and the like; organic bases such as triethylamine, tripropylamine, tributylamine and the like; etc.
• the amount of the compound of general formula [3] to be used is at least equimolar to the compound of general formula [2], preferably 1.0-6.0 moles per mole of the compound of general formula [2].
• the amount thereof is at least equimolar to the compound of general formula [2].
• reaction temperature and time are not critical; however, the reaction may be carried out at 20°-150° C. for 10 minutes to 10 hours.
• a compound of general formula [lb] can be obtained by reacting a compound of general formula [1a] with a halogenating agent such as carbon tetrabromidetriphenyl phosphine or the like in the presence or absence of a solvent.
• a halogenating agent such as carbon tetrabromidetriphenyl phosphine or the like in the presence or absence of a solvent.
• the solvent to be used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, halogenated hydrocarbons such as methylene chloride, chloroform and the like; ethers such as tetrahydrofuran, dioxane and the like; nitriles such as acetonitrile, propionitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; phosphates such as triethyl phosphate and the like; pyridine; etc. These solvents may be used alone or in admixture of two or more.
• halogenated hydrocarbons such as methylene chloride, chloroform and the like
• ethers such as tetrahydrofuran, dioxane and the like
• nitriles such as acetonitrile, propionitrile and the like
• amides such as N,N-dimethylformamide
• the amount of the halogenating agent to be used is at least equimolar to the compound of the compound of general formula [la], preferably 1.0-3.0 moles per mole of the compound of general formula [la].
• reaction temperature and time are not critical; however, the reaction may be carried out at 0°-60° C. for 5 minutes to 10 hours.
• a compound of general formula [lc] can be obtained by reacting the compound of general formula [lb] with a compound of general formula [4] in the presence or absence of a solvent.
• the solvent to be used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, halogenated hydrocarbons such as chloroform, methylene chloride, dichloroethane and the like; ethers such as tetrahydrofuran, dioxane and the like; aromatic hydrocarbons such as toluene, xylene and the like; nitriles such as acetonitrile, propionitrile and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; phosphoramides such as hexamethylphosphoramide, and the like; sulfoxides such as dimethyl sulfoxide and the like; etc. These solvents may be used alone or in admixture of two or more. It may also be used as a solvent for the compound of general formula [4].
• halogenated hydrocarbons such as chloroform, methylene chloride, dichloroethan
• the amount of the compound of general formula [4] to be used is at least equimolar to the compound of general formula [lb].
• reaction temperature and time are not critical; however, the reaction may be carried out at 10°-130° C. for 30 minutes to 48 hours.
• a compound of general formula [le] can be obtained by reacting a compound of general formula [ld] with a compound of general formula [5] in the presence or absence of a solvent.
• the solvent to be used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, the solvents mentioned in Production Process 3.
• the reaction can also be effected in the presence of a base.
• the base which may be used in the reaction includes, for example, the bases mentioned in Production Process 1 above, sodium hydride and the like.
• the amount of the compound of general formula [5] to be used is at least equimolar to the compound of general formula [ld], preferably 1.0-3 moles per mole of the compound of general formula [ld].
• the amount thereof may be at least equimolar to the compound of general formula [ld].
• reaction temperature and time are not critical; however, the reaction may be effected at 10°-140° C. for 10 minutes to 48 hours.
• a compound of general formula [lf] or [lg] can be obtained by oxidizing a compound of general formula [6] or [7] (dehydrogenation). These reactions are effected by processes known per se or their appropriate combinations, for example, according to the method described on pages 844-860 or 1088-1092 of Shin Jikken Kagaku Koza (New Experimental Chemistry Course), edited by Chemical Society of Japan published by Maruzen K. K., Vol. 15[I-2] or a method similar thereto.
• the above oxidation reaction may be effected using a dehydrogenating agent such as palladium-carbon, 2,3-dichloro-5,6-dicyano-p-benzoquinone, 2,3,5,6-tetrachloro-p-benzoquinone or the like.
• a dehydrogenating agent such as palladium-carbon, 2,3-dichloro-5,6-dicyano-p-benzoquinone, 2,3,5,6-tetrachloro-p-benzoquinone or the like.
• reaction temperature and time are not critical, and when palladium-carbon is used, the reaction may be carried out in a solvent such as cymene, decaline, cumene, diphenyl ether or the like at 150°-260° C. for 10 minutes to 48 hours.
• a solvent such as cymene, decaline, cumene, diphenyl ether or the like at 150°-260° C. for 10 minutes to 48 hours.
• 2,3-dichloro-5,6-dicyano-p-benzoquinone or 2,3,5,6-tetrachloro-p-benzoquinone is used, it is used in an amount of at least 2 moles per mole of the compound of general formula [6] or [7] and the reaction may be carried out in a solvent, for example, an aromatic hydrocarbon such as benzene, toluene, xylene, chlorobenzene, tert-butylbenzene, dichlorobenzene or the like; a halogenated hdyrocarbon such as chloroform, methylene chloride or the like; an organic acid such as acetic acid or the like; an alcohol such as tert-butyl alcohol or the like at 10°-180° C. for 10 minutes to 48 hours.
• a solvent for example, an aromatic hydrocarbon such as benzene, toluene, xylene, chlorobenzene, tert-butylbenzen
• the compound of general formula [lg] can be obtained by reacting the compound of general formula [7] with a halogen, for example, bromine, chlorine or the like.
• a halogen for example, bromine, chlorine or the like.
• the solvent to be used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, halogenated hydrocarbons such as carbon tetrachloride, chloroform, methylene chloride and the like. These solvents may be used alone or in admixture of two or more.
• the amount of halogen to be used is at least 2 moles per mole of the compound of general formula [7].
• reaction temperature and time are not critical; however, the reaction may be carried out at 0°-80° C. for 10 minutes to 48 hours.
• the compound of general formula [1] can also be produced by reacting a compound of general formula [8] with the compound of general formula [3] in the presence or absence of a solvent.
• the solvent used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane and the like; amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like; phosphoramides such as hexamethylphosphoramide and the like; sulfoxides such as dimethylsulfoxide; pyridine; and the like. These solvents may be used alone or in admixture of two or more.
• the compound of general formula [3] may also be used as a solvent.
• the amount of the compound of general formula [3] to be used is at least equimolar to the compound of general formula [8], preferably 1.0-20 moles per mole of the compound of general formula [8].
• reaction temperature and time are not critical; however, the reaction may be carried out at 50°-150° C. for 10 minutes to 10 hours.
• a compound of general formula [li] can be obtained by reacting a compound of general formula [lh] with a compound of general formula [9] or [10] in the presence or absence of a solvent.
• the solvent to be used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, the solvents mentioned in Production Process 2 above.
• the above reaction may also be effected in the presence of a base
• the base includes, for example, organic bases such as triethylamine, tripropylamine, tributylamine, pyridine and the like.
• the reaction may be effected in the presence of a Lewis acid such as aluminum chloride, dibutyltin diacetate or the like.
• the amount of the compound of general formula [9] or [10] used is at least equimolar to the compound of general formula [lh], preferably 1.0-10 moles, per mole of the compound of general formula [lh].
• reaction temperature and time are not critical; however, the reaction may be carried out at 20°-150° C. for 10 minutes to 10 hours.
• the salts may be used, and the above explanation of the salt of compound of general formula [1] can be applied thereto.
• R 1 , R 2 , R 3 , G and D have the same meanings as defined above
• R 2b represents a hydrogen atom or the unsubstituted or substituted lower alkyl, aryl or aralkyl group mentioned in the definition of R 2
• R 2c represents the unsubstituted or substituted lower alkyl or aralkyl group mentioned in the definition of R 2
• R 3a represents a hydrogen atom or the unsubstituted or substituted lower alkyl, alkenyl or aryl group mentioned in the definition of R 3
• R 6 represents an unsubstituted or substituted lower alkyl, aralkyl or aryl group or a group represented by the formula, --Y--Z in which Y and Z have the same meanings as defined above
• R 6a represents an unsubstituted or substituted lower alkyl, a
• R 2b , R 2c , R 3a , R 6 , R 6a , R 7 , R 8 , R 9 , and R 13 include those mentioned in the definitions of R 1 to R 5 .
• the reactive derivatives of the carboxylic acid of general formula [26] include symmetric acid anhydrides, mixed acid anhydrides, acid halides, active amides and the like.
• a compound of general formula [11] is reacted with a compound of general formula [12] to obtain a corresponding compound of general formula [13]
• a compound of general formula [14] is reacted with a compound of general formula [12] to obtain a compound of general formula [15] or [16]
• a compound of general formula [17] is reacted with a compound of general formula [18] to obtain a compound of general formula [19]
• a compound of general formula [17] is reacted with a compound of general formula [20] to obtain a compound of general formula [21] or [22].
• This reaction is generally called “Fisher's Indole synthesis” and is effected, for example, according to the process described on pages 1957-1960 of Shin Jikken Kagaku Koza (New Experimental Chemistry Course), edited by Chemical Society of Japan published by Maruzen K. K., Vol. 14[IV] or a process similar thereto.
• a compound of general formula [27] is obtained by reacting a compound of general formula [23] with a compound of general formula [24] (sulfonylation) to obtain a compound of general formula [25] followed by reaction with a reactive derivative of a carboxylic acid of general formula [26] and n-butyllithium.
• the reactive derivative of the carboxylic acid of general formula [26] may be replaced by a compound represented by the formula, R 8 -CN in which R 8 has the same meaning as defined above or N,N-dimethylformamide.
• a compound of general formula [27] is subjected to reaction with a compound of general formula [30] (the Wittig reaction) to obtain a compound of general formula [31] or a compound of general formula [25] is reacted with a compound of general formula [28] and n-butyllithium to obtain a compound of general formula [29], and then, the compound of general formula [29] is subjected to dehydration to obtain a compound of general formula [31].
• the group of the formula, --SO 2 R 7 in which R 7 has the same meaning as defined above may be replaced by a protective group usually used as a protective group for the imino group of indole ring, an alkyl group or the like.
• the compounds of general formulas [27] and [29] may be subjected to reaction with a compound of general formula [30] and dehydration reaction after the removal of protective group.
• a compound of general formula [39] can be obtained by subjecting the compound of general formula [32] or [34] to reaction with a compound of general formula [37] (the Diels-Alder reaction).
• the compound of general formula [31] can as such be subjected to reaction with maleic anhydride and then with an amine of general formula [35], or subjected to reaction with a compound of general formula [36] or [37] to obtain a compound of general formula [38] or [39] without being converted to the compound of general formula [32] or [34].
• a compound of general formula [40], [41] or [42] can be obtained by oxidizing the compound of general formula [13], [15], [16], [19], [21], [22], [38], [39] or [62] (dehydrogenation). These reactions are effected by processes known per se or their appropriate combinations, for exmaple, according to the method described in Shin Jikken Kagaku Koza (New Experimental Chemistry Course), Vol. 15[I-2], pages 844-860 or 1088-1092 or a method similar thereto.
• the compound of general formula [40], [41] or [42] can be obtained by reacting the compound of general formula [19], [21], [22], [38], [39] or [62] with a halogen, for example, bromine, chlorine or the like.
• a halogen for example, bromine, chlorine or the like.
• the solvent to be used in this reaction may be any solvent as far as it does not adversely affect the reaction, and includes, for example, halogenated hydrocarbons such as carbon tetrachloride, chloroform, methylene chloride and the like. These solvents may be used alone or in admixture of two or more.
• the amount of halogen to be used is at least 2 moles per mole of the compound of general formula [19], [21], [22], [38], [39] or [62].
• reaction temperature and time are not critical; however, the reaction may be carried out at 0°-80° C. for 10 minutes to 48 hours.
• a compound of general formula [46] can be obtained by reacting a compound of general formula [43] with a compound of general formula [30] or reacting a compound of general formula [44] with a compound of general formula [45]. This reaction is effected by processes known per se or their appropriate combinations, for example, according to the method described in Organic Reactions, Vol. 14, Chapter 3 or a method similar thereto.
• a compound of general formula [46] is subjected to reaction with maleic anhydride followed by reaction with a compound of general formula [35a], or a compound of general formula [46] is subjected to reaction with a compound of general formula [36a] to obtain a compound of general formula [50].
• a compound of general formula [46] is subjected to reaction with a compound of general formula [37] to obtain a compound of general formula [47].
• This reaction is effected by processes known per se or their appropriate combinations, for example, according to the method described in Organic Reactions, Vol. 4, Chapters 1 and 2 or a method similar thereto.
• a compound of general formula [53] is subjected to reaction with a compound of general formula [54] in the presence of boron trifluoride to obtain a compound of general formula [55].
• This reaction is effected by processes known per se or their appropriate combinations, for example, according to the method described in Chem. Ber., Vol. 97, pages 667-681 (1964) or a method similar thereto.
• the compound of general formula [55] is subjected to reaction with a compound of general formula [56] to obtain a compound of general formula [57].
• This reaction is effected by processes known per se or their appropriate combinations, for example, according to the method described in J. Chem. Soc., Perkin Trans. I, pages 2505-2508 (1985) or a method similar thereto.
• a compound of general formula [59] can be obtained by reacting a compound of general formula [58] with a reactive derivative of the carboxylic acid of general formula [26] and n-butyllithium.
• the compound of general formula [59] is subjected to reaction with a compound of general formula [30] (the Wittig reaction) to obtain a compound of general formula [61], or the compound of general formula [58] is reacted with the compound of general formula [28] and n-butyllithium to obtain a compound of general formula [60] followed by dehydration thereof to obtain a compound of general formula [61].
• a compound of general formula [30] the Wittig reaction
• the compound of general formula [58] is reacted with the compound of general formula [28] and n-butyllithium to obtain a compound of general formula [60] followed by dehydration thereof to obtain a compound of general formula [61].
• a compound of general formula [64] can be obtained by oxidizing a compound of general formula [63].
• This reaction is effected by processes known per se or their appropriate combinations, for example, according to the method described in Shin Jikken Kagaku Koza (New Experimental Chemistry Course), Vol. 14[III], pages 1749-1752 and 1760-1761 or a method similar thereto.
• a compound of general formula [2] can be obtained by hydrolyzing the compound of general formula [40], [41], [42], [49], [52], [57] or [64] and then dehydrating the product with acetic anhydride or the like.
• This reaction is effected by processes known per se or their appropriate combinations, for example, according to the method described in Organic Syntheses, Col. Vol. II, pages 457-458 and Col. Vol. I, page 410 or a method similar thereto.
• the salts may be used instead thereof, and the explanation of the salt of the compound of general formula [1] can be applied thereto.
• the compound of this invention (general formula [1]) thus obtained and the starting compounds thus obtained can be converted to other compounds falling within the scope of the same general formulas by being subjected to reactions known per se such as oxidation, reduction, rearrangement, substitution, acylation, halogenation, alkylation, imide-exchange, quaternization, deprotection, dehydration and hydrolysis or appropriate combinations of them.
• reaction mixtures may be used as they are without being subjected to isolation.
• the compounds of this invention (general formula [1]) thus obtained and the starting compounds thus obtained can be isolated and purified by a conventional method such as extraction, column chromatography, distillation, recrystallization or the like.
• the compound of this invention (general formula [1]) is used as a drug
• the compound can be orally or parenterally administered as it is or in admixture of a pharmaceutically acceptable additive, such as excipient, carrier, diluent or the like in the form of a tablet, capsule, diluent or the like in the form of a tablet, capsule, granule, powder, injection, suppository or the like.
• a pharmaceutically acceptable additive such as excipient, carrier, diluent or the like in the form of a tablet, capsule, diluent or the like in the form of a tablet, capsule, granule, powder, injection, suppository or the like.
• the dose of the compound is administered in one portion or several portions. However, the dose may be selected depending upon the age, weight and symptom of a patient.
• test compounds used were shown in Table 1a and Table 1b.
• R 1 and R 2 columns each represent a substitution site of substituent in carbazole skeleton, 1H-benzofuro[3,2-e]isoindole skeleton or 1H-[1] benzothieno[3,2-e] isoindole skeleton.
• Me methyl group
• Et ethyl group
• Pr n-propyl group
• i-Pr isopropyl group
• Bu n-butyl group
• t-Bu tert-butyl group
• Ph phenyl group
• Ac acetyl group.
• R 1 , R 2 , R 3 , G, Y and Z in Tables 1a and 1b refer to the respective substituents in the following formula for the test compounds:
• a test compound was appropriately diluted with a liquid medium (a minimum essential medium containing a 10% fecal calf serum).
• the resulting liquid was poured into each well of a 96-well micro titer plate, in an amount of 0.1 ml/well.
• HeLa S-3 cells were diluted with the same liquid medium so that the cell concentration became 2 ⁇ 10 4 cells/ml, and the resulting liquid was poured into each well of the above plate in an amount of 0.1 ml/well.
• the resulting plate was allowed to stand in a CO 2 gas incubator of 37° C. for 4 days, to effect incubation. After the incubation, the supernatant liquid in each well was removed and fixation by ethanol was effected for 10 minutes.
• the fixed cells were tinted with a Giemsa's staining solution to determine the minimum growth inhibition concentration (MIC) of test compound for HeLa S-3 cells.
• MIC minimum growth inhibition concentration
• Compound No. 23 (70 mg/kg) or Compound No. 28 (100 mg/kg) each dissolved in an aqueous 5% glucose solution was administered once to ddY strain mice in groups of 6 members (male, 4-week old) intravenously at the tail. However, no dead case was observed.
• the compound of the general formula [1] according to this invention has excellent antitumor activity and low toxicity.
• Kieselgel 60, Art. 7734 manufactured by Merck was used as a column filler, and the mixing ratio of eluant is expressed by volume in all cases.
• each solvent name in parenthesis in melting point column refers to a recrystallization solvent.
• Me methyl group
• Et ethyl group
• Pr n-propyl group
• i-Pr isopropyl group
• Bu n-butyl group
• t-Bu tert-butyl group
• Ac acetyl group
• Ph phenyl group
• IPA isopropyl alcohol
• nPA n-propyl alcohol
• AcOEt ethyl acetate
• Et 2 O diethyl ether
• R 1 and R 2 refer to the respective substituents in the compound represented by the following formula.
• N-benzyl-1,2,3,4-tetrahydrocarbazole-3,4-dicarboximide 150 mg was dissolved in 5 ml of methylene chloride. To this solution was added 220 mg of 2,3-dichloro-5,6-dicyano-p-benzoquinone (abbreviated to hereinafter as DDQ). The mixture was stirred at room temperature for 10 minutes. Then, thereto were added 20 ml of methylene chloride and 10 ml of an aqueous 10% potassium carbonate solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from n-propanol to obtain 120 mg (yield: 81%) of N-benzylcarbazole-3,4-dicarboximide as orange needles.
• DDQ 2,3-dichloro-5,6-dicyano
• R 1 and R 2 in Table 6 and R 1 in Table 7 refer to the respective substituents in the compounds represented by the following formulas.
• N-benzyl carbazole-3,4-dicarboximide To 330 mg of N-benzyl carbazole-3,4-dicarboximide were added 5 ml of dioxane and 1.0 ml of a 5 N aqueous sodium hydroxide solution. The mixture was refluxed for 30 minutes. Thereto was added 3.0 ml of concentrated hydrochloric acid. The resulting mixture was refluxed for 2 hours and then cooled to room temperature. Thereto were added 30 ml of ethyl acetate and 20 ml of water. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.
• R 1 and R 2 refer to the respective substituents in the compound represented by the following formula.
• R 1 refers to the corresponding substituent in the compound represented by the following formula.
• Diethyl 6-chloro-1,2,3,4-tetrahydrocarbazole-2,3-dicarboxylate was subjected instead of the N-benzyl-1,2,3,4-tetrahydrocarbazole-3,4-dicarboximide to the same reaction as in Reference Example 1 (3), to obtain diethyl 6-chlorocarbazole-2,3-dicarboxylate as colorless crystals.
• R 1 refers to the corresponding substituent in the compound represented by the following formula.
• R 1 and R 3 refer to the respective substituents in the compound represented by the following formula.
• R 1 and R 3 refer to the respective substituents in the compound represented by the following formula.
• R 1 in Table 13 and R 1 and R 3 in Table 14 refer to the respective substituents in the compounds represented by the following formulas.
• R 1 , R 2 , R 8 and R 9 refer to the respective substituents in the compound represented by the following formula.
• the oily material was dissolved in 20 ml of acetone. Thereto were added 350 mg of potassium hydroxide (purity: 90%) and 0.37 ml of benzyl bromide. The mixture was stirred at room temperature for 30 minutes. 70 ml of toluene was added to the mixture. The insoluble material was removed by filtration. The filtrate was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.
• R 1 , R 8 and R 9 refer to the respective substituents in the compound represented by the following formula.
• R 2 , R 8 and R 9 refer to the respective substituents in the compound represented by the following formula.
• R 1 , R 8 and R 9 refer to the respective substituents in the compound represented by the following formula.
• the resulting mixture was adjusted to pH 7.0 with 1 N hydrochloric acid.
• the organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate.
• the solvent was removed by distillation under reduced pressure.
• the residue was mixed with 990 mg of N-phenylmaleimide and 10 ml of xylene, and the mixture was refluxed for 1 hour. The solvent was removed by distillation under reduced pressure.
• R 1 , R 2 , R 6a , R 8 and R 9 refer to the respective substituents in the compound represented by the following formula.
• N-benzyl-9-benzyl-1-phenylcarbazole-3,4-dicarboximide was dissolved in 30 ml of benzene. Thereto was added 240 mg of anhydrous aluminum chloride. The mixture was stirred at room temperature for 3 hours, washed with water and an aqueous saturated sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue was recrystallized from n-propanol to obtain 140 mg (yield: 78%) of N-benzyl-1-phenylcarbazole-3,4-dicarboximide as yellow crystals.
• R 1 , R 2 , R 8 and R 9 refer to the respective substituents in the compound represented by the following formula.
• R 9 refers to the corresponding substituent in the compound represented by the following formula.
• the aqueous layer was extracted with 100 ml of diethyl ether, and the extract was combined with the previously separated organic layer.
• the combined solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate.
• the solvent was removed by distillation under reduced pressure.
• R 1 , R 8 and R 9 refer to the respective substituents in the compound represented by the following formula.
• a mixture of 5.0 g of 1-nitro-2-(1,3-pentadienyl)benzene and 2.9 g of maleic anhydride was stirred at 150° C. for 5 hours. Thereto were added 150 ml of toluene and 3.2 ml of benzylamine. The resulting mixture was azeotropically refluxed for 2 hours, and then cooled to room temperature. Thereto were added 150 ml of ethyl acetate and 100 ml of water. The organic layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.
• R 1 , R 8 and R 9 refer to the respective substituents in the compound represented by the following formula.
• R 1 , R 8 and R 9 refer to the respective substituents in the compound represented by the following formula.
• R 1 , R 8 and R 9 refer to the respective substituents in the compound represented by the following formula.
• R 3 refers to the corresponding substituent in the compound represented by the following formula.
• R 3 refers to the corresponding substituent in the compound represented by the following formula.
• R 3 refers to the corresponding substituent in the compound represented by the following formula.
• Indoleacetic acid was reacted with acetic anhydride in the presence of boron trifluoride to obtain 1-methylpyrano[3,4-b]indol-3-one.
• the product was reacted with dimethyl acetylenedicarboxylate to obtain dimethyl 1-methylcarbazole-2,3-dicarboxylate.
• R 1a , R 3a , R and G refer to the respective substituents in the compound represented by the following formula.
• R 1a , R 3a , R and G refer to the respective substituents in the compound represented by the following formula.
• R 1a , R 3a and G refer to the respective substituents in the compound represented by the following formula.
• the resulting mixture was adjusted to pH 7.0 with diluted hydrochloric acid.
• the organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate.
• the solvent was removed by distillation under reduced pressure.
• the residue was dissolved in 190 ml of methylene chloride.
• To the solution was added 29.8 g of triethylamine, and to the resulting mixture was dropwise added 16.9 g of methanesulfonyl chloride in 20 minutes with stirring at 0° C. The resulting mixture was stirred for 20 minutes at room temeprature.
• R 1 , R 3 , Y and Z in Table 32 and R 1 in Table 33 refer to the respective substituents in the compounds represented by the following formulas.
• R 1 , R 2 , R 3 , Y and Z refer to the respective substituents in the compound represented by the following formula.
• R 2 refers to the corresponding substituent in the compound represented by the following formula.
• R 1 , R 2 , R 3 , Y and Z in Table 36 and R 1 in Table 37 refer to the respective substituents in the compounds represented by the following formulas.
• a mixture of 210 mg of N-(2-dimethylaminoethyl)-6,7-dimethoxycarbazole-3,4-dicarboximide and 1.66 g of pyridine hydrochloride was sealed in a tube and stirred at 200°-210° C. for 2 hours. Then, 150 ml of water and 100 ml of ethyl acetate were added to the reaction mixture to dissolve the mixture. The solution was adjusted to pH 8.5 with potassium carbonate. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous potassium carbonate. The solvent was removed by distillation under reduced pressure.
• Example 1 (2) The following compounds were obtained in the same manner as in Example 1 (2), or (1) above and Example 1 (2):
• the residue was mixed with 50 ml of acetic acid, and the mixture was concentrated to dryness under reduced pressure. This procedure was conducted two more times to remove water. To the residue were added 130 ml of acetic acid and 6.64 g of cyclohexanone, and the mixture was refluxed for 2 hours. While the mixture was hot, the resulting insoluble material was removed by filtration. The filtrate was concentrated to dryness under reduced pressure. The residue was mixed with 200 ml of ethyl acetate and 200 ml of water. The mixture was adjusted to pH 7.5 with an aqueous saturated sodium hydrogencarbonate solution. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate.
• the solvent was removed by distillation under reduced pressure.
• the first obtained fraction was concentrated to dryness under reduced pressure.
• the residue was recrystallized from toluene to obtain 180 mg (yield: 1.7%) of N-(2-dimethylaminoethyl)-5,6,7,8-tetrahydrocarbazole-3,4-dicarboximide as yellow needles.
• the later obtained fraction was concentrated to dryness under reduced pressure.
• R 1 , R 3 , Y and Z refer to the respective substituents in the compound represented by the following formula.
• R 1 , R 3 , Y and Z in Table 39 and R 1 and R 3 in Table 40 refer to the respective substituents in the compounds represented by the following formulas.
• R 1 , R 3 , Y and Z refer to the respective substituents in the compound represented by the following formula.
• R 1 , R 3 , Y and Z refer to the respective substituents in the compound represented by the following formula.
• R 1 and R 3 refer to the respective substituents in the compound represented by the following formula.
• R 1 , R 3 , G, Y and Z refer to the respective substituents in the compound represented by the following formula.
• the residue was mixed with 100 ml of ethyl acetate and 50 ml of an aqueous saturated sodium hydrogencarbonate solution. The mixture was stirred for 30 minutes. The resulting insoluble material was removed by filtration. The separated insoluble material was washed with 50 ml of ethyl acetate. The filtrate and the washings were combined. The organic layer was separated, washed with an aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure.
• R 1 , R 3 , Y and Z refer to the respective substituents in the compound represented by the following formula.
• R 1 , R 3 , Y and Z refer to the respective substituents in the compound represented by the following formula.
• the kneaded product was subjected to granulation process to obtain powder, dried, mixed with 0.6 g of magnesium stearate, and formulated into tablets (110 mg/tablet).

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